On average, >90% of patients who suffer from a cardiac arrest die. Nearly all die unexpectedly from this leading cause of death, in part, because the essential components of standard CPR (S-CPR): manual chest compressions at a rate of 100/min, 1 to 1.5 inches in depth and positive pressure ventilations, are an inherently inefficient process, providing less than 25% of normal blood flow to the heart and brain. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application builds upon our new understanding of ways to optimize blood flow to the heart and brain during CPR and protect these organs from reperfusion injury. It promises to provide new hope for patients who suffer from sudden cardiac death. The proposed research is focused on demonstrating proof of concept that reducing or preventing reperfusion injury by ischemic postconditioning (PC) is both feasible and critical to markedly enhancing survival with favorable neurological function after cardiac arrest. Building upon recent and significant advances in the treatment of cerebral and cardiac ischemia, where controlled reperfusion has been shown to strikingly reduce stroke and infarct size in patients with cerebral vascular events and myocardial infarction, we have recently temporarily restricted blood flow during the first three minutes of CPR in a pig model of prolonged untreated cardiac arrest. The results have been striking: after 15 minutes of untreated ventricular fibrillation, performing CPR with a number of defined and controlled pauses during the first three minutes of circulation in conjunction with a means to optimize blood flow to the heart and brain during CPR has normalized brain and heart function < 24-hours after arrest. These exciting observations contradict what was previously thought impossible; to restore full life in the setting of prolonged absence of flow and severe metabolic derangement. While antithetical to current practice, this novel approach that significantly reduces and in some cases prevents reperfusion injury may result in a novel and clinically important method of CPR that is easy to implement by EMS personnel and in the home. It provides the promise, based upon sound physiological principles and concepts, to markedly improve neurologically intact survival in patients that have heretofore never been possible to resuscitate. In this application we propose to further explore these findings. In the current application we propose to a) verify that the anticipated improvement in circulation and resuscitation rates can be translated into neurologically intact survival in animal models of cardiac arrest, and b) design and prototype a tool to help perform CPR with PC. If successful, this therapy will result in saving >10,000 more Americans each year from out of hospital cardiac arrest and a similar number of in-hospital survivors based upon the superior blood flow and the ability afforded by PC to protect the brain and heart from reperfusion injury during CPR. PUBLIC HEALTH RELEVANCE: Based upon a combination of multiple newly discovered mechanisms to enhance circulation during CPR, in the current application we propose to a) verify that after prolonged untreated cardiac arrest, controlled re-introduction of blood flow with postconditioning (controlled CPR pauses) combined with a superior hemodynamic method of CPR can be translated into higher rates of neurologically intact survival in animal models of cardiac arrest, and b) develop a CPR device that provides continuous user feedback on quality of CPR and guides the user to perform a novel type of CPR which is key to improving brain and heart blood flow during cardiac arrest with the goal of improving neurologically intact survival. This technology is needed because high quality STD CPR provides less than 20% of normal blood flow to the heart and little more to the brain. Even in the most efficient emergency medical systems, less than 20% of all patients with an out-of-hospital cardiac arrest are discharged from the hospital with intact neurological function. Strikingly, the average national survival to hospitl discharge after out-of-hospital cardiac arrest has remained less than 5% for decades. This complex disease state remains the nation's #1 killer, claiming more than 1000 lives outside the hospital and 1000 lives inside the hospital each day in the United States alone. Improved circulation to the brain and other vital organs during CPR, especially when combined in an overall systems-based approach to pre and post-resuscitation care, has the potential to significantly reduce morbidity and mortality from cardiac arrest.